Keto aliphatic acid esters and method of preparing the same



KETOALIPHATIC ACID ESTERS AND METHOD F PREPARING THE SAME Mil0n W. Bullock, Pearl River, N. Y., assignor to American 'Cyanamid Company, New York, N. Y., a corporation of -Maiue I V Ni) Drawing. Applicationfictober 19, 1953 Serial No. 387,025

14 Claims. (Cl. 260-399) This invention relates to new organic compounds.

Moreiparti'cularly, it relates to thiosubstitu'ted keto aliphatic acid esters and methods of preparing the same.

In my copending application, Serial Number 284,205, filed April2'4, 1952, I describe the preparation of omegai[3-(l,2-dithiolarnyl)] aliphatic acids, salts and esters thereof. These compounds were described as oxidation inhibitors and growth supporting factors for certain microorganisms including S. :jacelis, Tetrahymena geleii and sofneCorynebacterium species. Also, disclosed in the said application was the use of thiosubstituted keto aliphatic 'acid esters as intermediates in the preparation of new active compounds. The present application is a continuation-in-part-of application, Serial Number 284,205 and describes and claims the said intermediates.

The new compounds of the present invention may be illustrated by the following structural formula:

in WhlChR is a lower alkyl radical, R and R" are hydrogen or lower alkyl radicals, R is an alkyl, monocyclic aryl substituted lower alkyl or lower fatty acid acyl radical and n is'a whole number less than 7. The alkyl radicals represented by R, R and R" can be methyl, ethyl, propyl, but-yl, isobutyl, amyl, etc. 12" can be radicals such as methyl, ethyl, propyl, butyl, decyl, dodecyL'heptadecyl, octadecyl, benzyl, phenethyl, acetyl, propionyl butyryl, and the like.

The compounds o'f'the present invention are, in general, liquids'at'room temperature, although in some cases they are comparatively low melting crystalline solids. are immiscible with water and soluble or miscible with general organic solvents such as acetone, chloroform, ether, and the like.

To prepare the compounds of the present invention it is preferred that unsaturated aliphatic acid esters. such as iho'se'described'in by copending application, Serial Number 387,024, filed October 19, 1953, be used as intermediates. These acid esters are reacted with thioacids such as thioacetic acid, thiopropionic acid, thiobutyric acid or a mercaptan such as benzyl mercaptan, methyl mercaptan, ethyl mercaptan, propyl mercaptan, decyl mercaptan, ,dodecyl mercaptan, heptadecyl mercaptan, octadecyl niercaptan, and the like.

The reaction to prepare the compounds of the present invention may be illustrated as follows:

They

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2 reaction is spontaneous and exothermic when using thioacids, however, to insure complete reaction it is usually desirable to heat the reaction mixture for a short period of time. When 'mercaptans are used it is advantageous to use an alkaline catalyst :such as sodium hydride or sodium ethoxide. The temperature at which the reaction is .run is not critical. However, I prefer a temperature of 30 to C.

When the reaction is complete the catalyst '(if present) is removed by Washing with water and the excess of mercaptan -or thioacid is distilled off under reduced pressure. The product can then be purified by distillation under reduced pressure. Alternatively, when the product is a solid it can be purified by crystallization from suitable solvents.

The following examples illustrate in detail the process of the present invention wherein thiosubstituted .keto acid esters are prepared. Example 1- No. Boiling "Pressure,

Pointmm.

Example 2 To 8.0 g. (0.0435 mole) of ethyl-A ,6-ketooctenoate contained in a 50 ml. flask equipped with a condenser was added 3.62 g. (0.048 mole) of thioacetic acid. The reaction was rapid and exothermic. The excess thioacetic acid was distilled off under the reduced pressure of an aspirator. The product obtained was identical with that of Example 1.

' Example 3 Thirty-five ml. of thioacetic acid was added to 60 g. of ethyl-A ,5-ketoheptenoate which had partially polymerized from long storage. Afterthe exothermic reaction had subsided, the mixture was warmed on the steam bath one hour. The excess thioacetic acid was distilled off and the residue purified by vacuum distillation. The fraction distilling 143 l45 at 0.05 mm. and weighing 32 g. was collected as product. The product crystallized on storage in the cold room. The long white needles were filtered from a small amount of oil and washed generously with cold ligroin. The pure crystals of ethyl- 7-acetylthio-S-ketoheptanoate, melting point 18.5 This material had n 1.4801 and d 1.110.

Example 4 One hundred twenty-nine and three-tenths grams (0.69 mole) of the ethyl-A",6-ketononenoate were placed in a 3 250 ml. round bottom flask equipped with condenser and dropping funnel. The flask was swirled while 55 ml. (0.705 mole) of thioacetic acid was added to 5 ml. portions. The reaction was sufficiently exothermic that the temperature rose to approximately 100. The reaction mixture was heated on the steam bath one-half hour and the excess thioacetic acid distilled off under the reduced pressure of an aspirator. The product was vacuum distilled through a six inch vacuum jacketed Vigreux Column. After a fairly large forerun, which was two phases (the upper phase was a hydrocarbon impurity which was formed by the polymerization of the propylene during the condensation reaction), the remainder of the product distilled 140 at 0.05 mm. and had n 1.4772, d 1.071. An additional 13.5 g. of product was obtained by distilling the lower phase of the forerun bringing the total yield of pure ethyI-S-acetylthio-fi-ketononanoate to 141.4 g. (0.515 mole), 75%.

' Example 5 In a liter pot were placed 185 g. (1.5 moles) of benzyl mercaptan and about mg. of sodium hydride. After most of the sodium hydride had reacted 244 g. (1.43 moles) of methyl-A",6-ketooctenoate was added. After the exothermic reaction had subsided the reaction mixture was heated on the steam cone one hour. The reaction mixture was cooled, diluted with an equal volume of chloroform and washed once with water. The chloroform solution was dried over sodium sulfate and the solvent distilled. Distillation yielded 303.4 g. (1.03 moles), 72% of methyl-8-benzylthio-6-ketooctenoate, boiling point 175 at 0.1 mm., n 1.5291, @1 1.100.

Example 6 In a 250 ml. flask was placed 42.5 g. (0.343 mole) of benzylmercaptan and 100 m of sodium hydride. After most of the sodium hydride had reacted g. (0.303 mole) of ethyl-A ,6-ketononenoate was added. The reaction mixture was warmed on the steam bath one hour and left standing at room temperature over the weekend. The reaction mixture was dissolved in 250 ml. ether and the ether solution washed with 5% sodium hydroxide, water and saturated sodium bicarbonate solution. Distillation of the dried sodium sulfate left 93 g. of oil which was purified under reduced pressure. The fraction distilling 180 at 0.07 mm. was collected as product. of ethyl-8benzylthio-6-ketononanoate was 75.5 g. (0.234 mole), 77.4%. The product had n 1.5192 and d 1.059.

Example 7 In a 300 ml. round bottom flask equipped with condenser was placed 182 g. (1.07 moles) of methyl-11 ,6- ketooctenoate. The reaction flask was swirled and cooled in a water bath while 93.5 g. (1.23 moles) of thioacetic acid was added in small portions through the condenser.

The reaction mixture was left standing two hours and the product vacuum distilled. The product, methyl-8- acetylthio-6-ketooctan-oate distilled 138140 at 0.1 mm. The yield was 250 g. (1.015 mole), 94.6%. The material had n 1.4810 before it crystallized to a white solid having melting point 37.

Example 8 The yield Example 9 In a 500 ml. round bottom flask equipped with condenser were placed g. (1.73 moles) of ethyl mercaptan and approximately 200 mg. of sodium hydride. After a few minutes the flask was cooled in an ice bath and 170 g. (1 mole) of methyl A ,6-ketooctenoate was added to the mixture. After the initial exothermic reaction subsided, the reaction mixture was heated at reflux temperature four hours and the excess ethyl mercaptan distilled off. The product was purified by distillation. The fraction distilling 126 at 0.15 mm. was collected as product. The pure methyl S-ethylthio-G-ketooctanoate had 11 1.4771 and d 1.051. The yield was 212.8 g. (0.92 mole), 92%.

Example 10 In a liter flask were placed 200 g. (0.99 mole) of dodecyl mercaptan and about 100 mgs. of sodium hydride. After a few minutes 179.3 g. (0.98 mole) of ethyl A",6- ketooctenoate was added. The reaction mixture was heated on the steam bath two hours and left standing overnight. The crystals were filtered off and washed with ligroin. The yield of the crude crystals was 98 gymelting at 60-62. The product melted 6465 after recrystallization from ligroin. More product was obtained by distilling the material which did not crystallize. The product distilled 168172 at 0.09 mm. and solidified on cooling. The total yield of purified ethyl 8-dodecylthio- 6-ketooctanoate was 198 g. (0.512 mole), 50%.

I claim:

1. Compounds having the general formula in which R is a lower alkyl radical and R is selected from a group consisting of lower alkanoyl, benzyl, and alkyl radicals of 1 to 12 carbon atoms, which comprises reacting a compound having the formula in which R is as defined above with a compound having the formula HSR in which R is as defined above. I

9. A method of preparing a lower alkyl ester of 8 j lower alkanoylthio-o-ketooctanoic acid which comprises reacting a lower alkyl ester of AZG-k'etooctenoate with a lower alkanoylthiol acid.

10. A method of preparing a lower alkyl ester of 8 acetylthio--ketooctanoic acid which comprises reacting a lower alkyl ester of.A",6-ketooctenoate with thioacetig acid.

11. A method of preparing ethyl 8-acetylthio6-ketooctanoate which comprises reacting ethyl A",6-ketoo.ctenoate with thioacetic acid.

12. A method of preparing methyl-8-benzylthio- 6;-

.ketooctanoate which comprises reacting methyl A",6 -k etooctenoate-with benzyl mercaptan. I

2,828,821 5 6 13. A method of preparing methy1-8-acetylthio-6-keto- 2,568,648 McCool Sept. 18, 1951 octanoate which comprises reacting methyl A",6-ketooc 2,759,005 Starker et a1. Aug. 14, 1956 tenoate with thioacetic acid.

14. A method of preparing methy1-8-ethy1thio-6 -ket0- FOREIGN PATENTS octanoate which comprises contacting methyl A ,6-keto- 5 867,394 Germany 16, 1953 octanoate with ethanethiol in the presence of sodium hy- OTHER REFERENCES dude Svensk, Kern. Tid. 55, 168-171 (1943), Darstellung References Cited in the file of this Patent v von B-Merkaptoisobuttersiure, by E. Larsson.

Gilman: Organic Chemistry, 2nd edition, 1943, vol. 1, UNITED STATES PATENTS 10 pages 3 39 93 2,390,099 Harmon Dec. 4, 1945 Bullock et a1.: Journal of the American Chemical S0- 2,531,602 Bell Nov. 28, 1950 ciety, v01. 74, 3455 (1952). 

1. COMPOUNDS HAVING THE GENERAL FORMULA 